The present invention is directed to a process for 3R-(3-carboxybenzyl)-6-(5-fluoro-2-benzothiazolyl)-methoxy-4R-chromanol, of the formula ##STR1## alternatively named 3R,4R-[(3-carboxyphenyl]methyl)-6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4 -dihydro-2H-benzopyran-4-ol. In this process, the corresponding racemic compound, (.+-.)-cis-(3-carboxybenzyl)-6-(5-fluoro-2-benzothiazolyl)methoxy-4-chroma nol is resolved using quinine, with isolation of the pure, crystalline, less-soluble, diastereomeric quinine salt of (I) from methanol.
The compound (I) is a known inhibitor of 5-lipoxgenase enzyme and antagonist of leukotriene receptors, and so is valuable in the prevention or treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related disease states in mammals as detailed in published European patent application No. 313295.
The compound (I) was heretofore obtained via the methyl ester of the compound of the formula (I), which in turn had been obtained by resolution of the corresponding racemic compound via separation of diastereomeric R-0-acetylmandelate esters. This method involves the discrete chemical steps of esterification and hydrolysis. It has thus been a desirable goal to find a method for the direct resolution of the cis-acid in the form of a readily formed and decomposed diastereomeric salt, a goal which has been met by the present invention.
Quinine has been previously used in the resolution of racemic organic acids. However, its use does not assure success in any given instance, since it requires not only that the desired diastereomeric salt be crystalline, but that it be significantly less soluble than its structurally, closely related diastereomeric salt, if the desired salt is to be obtained in good yield without tedious fractional crystallization methods. See Wheland, "Advanced Organic Chemistry," 3rd Ed., John Wiley and Sons, Inc., New York, 1960, page 312; and "Left and Right Drugs," Science 84, American Association for the Advancement of Science, Washington, D.C., June, 1984, page 11.